EP0157235A1 - Procédé pour la préparation de protéines - Google Patents

Procédé pour la préparation de protéines Download PDF

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Publication number
EP0157235A1
EP0157235A1 EP85102802A EP85102802A EP0157235A1 EP 0157235 A1 EP0157235 A1 EP 0157235A1 EP 85102802 A EP85102802 A EP 85102802A EP 85102802 A EP85102802 A EP 85102802A EP 0157235 A1 EP0157235 A1 EP 0157235A1
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EP
European Patent Office
Prior art keywords
protein
biospecific
polypeptide
bound
short
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP85102802A
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German (de)
English (en)
Inventor
Günter Prof. Dr. Schmidt-Kastner
Carl Dr. Kutzbach
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
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Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0157235A1 publication Critical patent/EP0157235A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/20—Fusion polypeptide containing a tag with affinity for a non-protein ligand

Definitions

  • the invention relates to a process for the production of proteins by co-cloning DNA sequences for a desired protein with those for two specific further peptides by means of genetic engineering methods with expression of a combined protein from the three components.
  • This combined protein is then biospecifically adsorbed onto a carrier-bound, biospecific-complementary substance and, after separation from other constituents, is split up in such a way that only a few fragments are present, one of which is the desired protein.
  • the invention now provides a conceptually new method for the genetic engineering production and production of a protein.
  • the method of the invention thus includes the measure of not allowing the desired protein to be expressed in isolation, but combined with two other elements, the biospecific polypeptide and the short-chain peptide.
  • the short-chain peptide which is arranged between the desired protein and the biospecific polypeptide, represents the predetermined breaking point.
  • the short-chain peptide must therefore be such that it can be cut out in a highly specific manner in the later process. This cutting out is preferably done with an enzyme.
  • the choice of the short-chain peptide thus depends on whether an agent, for example an enzyme, is available which is able to recognize and cleave the amino acid sequence of the short-chain peptide. However, a one-sided cleavage of the bond between the short-chain peptide and the desired protein is also sufficient.
  • Such a highly specific enzyme is e.g. the pancreatic enzyme kallikrein (E.C. 3.4.21.8.). This enzyme cleaves the sequence of the decapeptide Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg from the peptide chain of the kininogen. According to the invention, this decapeptide is preferably co-cloned.
  • the further biospecific polypeptide co-cloned according to the invention has the task of binding to a carrier-bound, biospecific-complementary substance, so that the carrier can be separated from other components of the medium together with the combined protein bound to it. It follows that the biospecific polypeptide / complementary substance system must meet the requirement that a strong bond should occur between them under the given reaction conditions.
  • Biologically active polypeptides e.g. Enzymes can be biospecific with biologically active complementary substances, e.g. complexes with inhibitors, e.g. Form enzyme-inhibitor complexes.
  • biospecific enzyme-inhibitor complexes have a high binding affinity. Their dissociation constant is accordingly small.
  • an enzyme-inhibitor complex is the trypsin-aprotinin complex preferred according to the invention, which consists of the enzyme trypsin and the enzyme inhibitor Aprotinin is formed.
  • the trypsin-aprotinin complex is accordingly formed very quickly and has a very high stability under the given conditions.
  • the stability of the trypsin-aprotinin complex depends on the pH of the solution and decreases with decreasing pH. At a pH of approximately 2.0, the trypsin-aprotinin complex is almost completely dissociated.
  • Such behavior is particularly desirable in the context of the invention because it is easy to regenerate the carrier-bound complementary substance. This can then be used again in the process. It is also desirable that the rate of formation of the bond between the biospecific polypeptide and the carrier-linked complement is high. In this way, possible competitive reactions of the carrier-bound substance with other sites of the combined polypeptide can be reduced.
  • the described enzyme / inhibitor system is only exemplary.
  • the systems antigen / antibody or peptide hormone / receptor can also be used, for example.
  • the biospecific adsorption is preferably carried out using water-insoluble carriers to which the biospecific-complementary substance is bound. This binding can take place according to the known methods of immobilization with or without spacer molecules.
  • the DNA sequence of the three components mentioned are co-cloned using genetic engineering methods and the DNA thus obtained is transferred into the DNA of a host organism, for example into a plasmid, according to genetic engineering methods.
  • Suitable microorganisms can be used as the host organism, for example bacteria, in particular E. coli, but also Bac. subtilis or yeast.
  • the transcription, translation and ultimately the expression of the co-cloned DNA takes place during the cultivation of the microorganism.
  • the desired protein with the two co-cloned peptides is contained in the fermentation solution, the cells are separated, for example by centrifugation or by cross-flow filtration, and the culture filtrate is used for isolation.
  • the desired protein with the two co-cloned peptides is contained in the cell itself, the cells are separated, the cells disrupted and the cell fragments separated by separation.
  • the culture filtrate or the cell extract not only contain the desired co-cloned combined protein, but also a large number of other proteins, a large number of other products, but also adherent nutrient medium components.
  • the desired combined protein is now isolated and purified from this complex solution. This is done by taking the carrier-specific biospecific complementary substance, eg the immobilized trypsin to the culture filtrate or extract.
  • the water-insoluble complex is instantly formed from the five components at a high rate of complex formation: carrier + biospecific-complementary substance + biospecific polypeptide + short-chain peptide + desired protein, for example the complex from the five components carrier + trypsin + aprotinin + decapeptide + desired protein.
  • carrier + biospecific-complementary substance + biospecific polypeptide + short-chain peptide + desired protein for example the complex from the five components carrier + trypsin + aprotinin + decapeptide + desired protein.
  • the carrier-bound biospecific-complementary substance can be added at room temperature, but also, at the high rate of complex formation, at low temperatures, for example at + 2 ° C.
  • the water-insoluble complex can be separated from other proteins in the fermentation solution and also from all other impurities by simple filtration.
  • a proteolytic enzyme for example trypsin
  • it can be saturated with a low molecular weight inhibitor before being added to the fermentation solution.
  • the dissociation constant of the low molecular weight inhibitor must be greater than that of the biospecific polypeptide. Due to the different dissociation constants, the small molecule inhibitor is displaced by the biospecific polypeptide when the fermentation solution is added.
  • a low molecular weight inhibitor for the carrier-bound trypsin for example, benzamidine with a dissociation constant of 18.10 mol / 1 or phenylguanidine with a dissociation constant of 72. 10 -6 mol / 1 can be used.
  • the carrier-bound, biospecific-complementary substance can be filled into a column.
  • the culture filtrate or cell extract is then passed through the column.
  • only the desired combined protein is bound to the solid support via the biospecific polypeptide, while all other proteins and all other impurities pass through the column.
  • the biospecific-complementary polypeptide bound to the carrier should be saturated as completely as possible with the complex to be bound.
  • the column can be freed of residual adhering impurities by washing with buffer solutions or by washing with other suitable solutions. If the rate of complex formation is high, the column can also be loaded at low temperatures.
  • the combined protein bound to the carrier is broken down by the action of a specific enzyme, the specific enzyme cleaving exclusively the peptide bonds of the short-chain peptide.
  • the enzyme kallikrein can be used as the specific enzyme, as mentioned.
  • the kallikrein hydrolyzes the decapeptide on both sides and releases the terminally bound, desired protein from the combined protein.
  • a one-sided cleavage of the bond between a short-chain peptide and the desired protein is also sufficient.
  • Such a short chain peptide could e.g. B. contain only the last three C-terminal amino acids of the above decapeptide with the sequence Pro-Phe-Arg. So the kallikrein splits highly specific at the desired breaking point ... Arg-X ... the hepeptides: or
  • the desired protein is eluted together with the decapeptide and can be extracted from the decapeptide by known methods, e.g. by molecular sieve chromatography.
  • the desired protein is thus obtained in pure form.
  • the advantage in the choice of a short-chain peptide as the predetermined breaking point in the combined protein can be seen in the fact that, after cleavage, the desired protein, as a generally large molecule, can easily be separated from the small, short-chain peptide.
  • the biospecific polypeptide remains bound to the carrier via the complementary substance under the conditions of the elution. Only by changing e.g. the pH of a buffer solution, e.g. to a value of 2-3, the biospecific polypeptide is detached and washed out of the column. After further washing, the column can then be adjusted to a suitable pH with buffer solutions, to pH 8.0 when using trypsin / aprotinin, and used again for a further experiment.
  • Proteins which can be produced by the process according to the invention include polypeptide sequences of hormones, for example human somatotropin, erythropoitin, corticotropin, pre-pro-insulin, pre-minipro-insulin, A- and B- Chain of insulin, polypeptide sequences from neutrotransmitter, for example substance P or the ⁇ -endomorphine, polypeptide sequences of the interferons, of the INF- ⁇ , INF- ⁇ , INF- ⁇ , the hybrid interferons, the interleukins, polypeptide sequences of plasma proteins, for example the human ⁇ 1 - Antitrypsins, albumins, coagulation factors, eg tissue plasminogen activator, factor VIII, polypeptide sequences of enzymes, eg D-xylose isomerase, penicillin acylase, urokinase, Rennins, polypeptide sequences of antibodies, eg of monoclonal antibodies and of vaccines to name.
  • hormones for
  • Figure 1 illustrates the method according to the invention in a schematic form.

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  • Genetics & Genomics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP85102802A 1984-03-22 1985-03-12 Procédé pour la préparation de protéines Withdrawn EP0157235A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3410437 1984-03-22
DE19843410437 DE3410437A1 (de) 1984-03-22 1984-03-22 Verfahren zur herstellung von proteinen

Publications (1)

Publication Number Publication Date
EP0157235A1 true EP0157235A1 (fr) 1985-10-09

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ID=6231214

Family Applications (1)

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EP85102802A Withdrawn EP0157235A1 (fr) 1984-03-22 1985-03-12 Procédé pour la préparation de protéines

Country Status (7)

Country Link
EP (1) EP0157235A1 (fr)
JP (1) JPS60214897A (fr)
KR (1) KR850006550A (fr)
CA (1) CA1230840A (fr)
DE (1) DE3410437A1 (fr)
DK (1) DK129085A (fr)
IL (1) IL74661A0 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196056A2 (fr) * 1985-03-28 1986-10-01 Chiron Corporation Expression de gènes fusionnés pour la production de protéines
EP0207402A2 (fr) * 1985-07-03 1987-01-07 Bayer Ag Procédé de préparation de protéines et de polypeptides
EP0212285A1 (fr) * 1985-07-29 1987-03-04 Arthur A. Gottlieb Dérivation et utilisation de produits de gènes sélectionnés
GB2188322A (en) * 1986-03-26 1987-09-30 Bayer Ag Aprotinin and analogues thereof produced by a recombinant host
EP0241546A1 (fr) * 1985-10-11 1987-10-21 Genetics Institute, Inc. Procede de production de proteines heterologues
EP0244627A2 (fr) * 1986-04-10 1987-11-11 Bayer Ag Vecteurs d'expression pour la production de polypeptides
EP0286239A1 (fr) * 1987-03-10 1988-10-12 New England Biolabs, Inc. Production et purification d'une protéine fusionnée d'une protéine de liage
FR2615528A1 (fr) * 1987-05-18 1988-11-25 Pasteur Institut Procede de production d'un polypeptide ayant des proprietes choisies determinees, dans un organisme-hote transforme par un adn recombinant contenant des sequences nucleiques codant pour ce polypeptide et pour une proteine affine d'ose
WO1989002461A1 (fr) * 1987-09-18 1989-03-23 Schering Aktiengesellschaft Procede de production de peptides par clivage specifique de proteines de fusion avec des collagenases obtenues par ingenierie genetique
WO1990000609A1 (fr) * 1988-07-08 1990-01-25 The University Of British Columbia Proteines de fusion se liant a la cellulose
EP0372352A2 (fr) * 1988-12-06 1990-06-13 Chisso Corporation Aéquorine fusionnée avec une protéine ayant une activité de liaison spécifique, sa préparation, sa purification et méthode de détection l'utilisant
WO1991009125A1 (fr) * 1989-12-07 1991-06-27 British Bio-Technology Limited Proteines et acides nucleiques
US5032573A (en) * 1987-03-23 1991-07-16 Bayer Aktiengesellschaft Homologs of aprotinin produced from a recombinant host, process, expression vector and recombinant host therefor and pharmaceutical use thereof
WO1991011454A1 (fr) * 1990-01-24 1991-08-08 The Upjohn Company Procede de purification de polypeptides recombines

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8800981A (sv) * 1988-03-17 1988-10-14 Lars Abrahamsen A recombinant fusion protein, its use and a recombinant vector
KR100792510B1 (ko) * 2007-10-29 2008-01-08 이강운 직교 좌표형 로봇의 듀얼타입 테이블
CN103285814B (zh) * 2012-11-30 2015-07-08 西北大学 一种基于强螯合配体的固定金属亲和色谱固定相及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0009930A1 (fr) * 1978-10-10 1980-04-16 The Board Of Trustees Of The Leland Stanford Junior University DNA recombinant, méthode pour sa préparation et production de protéines étrangères par des hôtes unicellulaires le contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0009930A1 (fr) * 1978-10-10 1980-04-16 The Board Of Trustees Of The Leland Stanford Junior University DNA recombinant, méthode pour sa préparation et production de protéines étrangères par des hôtes unicellulaires le contenant

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0196056A2 (fr) * 1985-03-28 1986-10-01 Chiron Corporation Expression de gènes fusionnés pour la production de protéines
EP0196056A3 (en) * 1985-03-28 1987-12-23 Chiron Corporation Improved expression using fused genes providing for protein product
EP0207402A2 (fr) * 1985-07-03 1987-01-07 Bayer Ag Procédé de préparation de protéines et de polypeptides
EP0207402A3 (fr) * 1985-07-03 1988-06-08 Bayer Ag Procédé de préparation de protéines et de polypeptides
EP0212285A1 (fr) * 1985-07-29 1987-03-04 Arthur A. Gottlieb Dérivation et utilisation de produits de gènes sélectionnés
EP0241546A1 (fr) * 1985-10-11 1987-10-21 Genetics Institute, Inc. Procede de production de proteines heterologues
EP0241546A4 (fr) * 1985-10-11 1988-11-02 Genetics Inst Procede de production de proteines heterologues.
GB2188322A (en) * 1986-03-26 1987-09-30 Bayer Ag Aprotinin and analogues thereof produced by a recombinant host
EP0238993A2 (fr) * 1986-03-26 1987-09-30 Bayer Ag Homologues d'aprotinine produits par génie génétique
EP0238993A3 (en) * 1986-03-26 1989-03-22 Bayer Ag Aprotinin homologues produced by genetic engineering
US4894436A (en) * 1986-03-26 1990-01-16 Bayer Aktiengesellschaft Homologs of aprotinin produced from a recombinant host, process expression vector and recombinant host therefor and pharaceutical use thereof
EP0244627A2 (fr) * 1986-04-10 1987-11-11 Bayer Ag Vecteurs d'expression pour la production de polypeptides
EP0244627A3 (fr) * 1986-04-10 1989-03-22 Bayer Ag Vecteurs d'expression pour la production de polypeptides
EP0286239A1 (fr) * 1987-03-10 1988-10-12 New England Biolabs, Inc. Production et purification d'une protéine fusionnée d'une protéine de liage
US5032573A (en) * 1987-03-23 1991-07-16 Bayer Aktiengesellschaft Homologs of aprotinin produced from a recombinant host, process, expression vector and recombinant host therefor and pharmaceutical use thereof
WO1988009375A1 (fr) * 1987-05-18 1988-12-01 Institut Pasteur Procede de preparation de polypeptides par adn recombinants
EP0299810A1 (fr) * 1987-05-18 1989-01-18 Institut Pasteur Procédé de préparation de polypeptides par ADN recombinant
FR2615528A1 (fr) * 1987-05-18 1988-11-25 Pasteur Institut Procede de production d'un polypeptide ayant des proprietes choisies determinees, dans un organisme-hote transforme par un adn recombinant contenant des sequences nucleiques codant pour ce polypeptide et pour une proteine affine d'ose
WO1989002461A1 (fr) * 1987-09-18 1989-03-23 Schering Aktiengesellschaft Procede de production de peptides par clivage specifique de proteines de fusion avec des collagenases obtenues par ingenierie genetique
WO1990000609A1 (fr) * 1988-07-08 1990-01-25 The University Of British Columbia Proteines de fusion se liant a la cellulose
EP0372352A2 (fr) * 1988-12-06 1990-06-13 Chisso Corporation Aéquorine fusionnée avec une protéine ayant une activité de liaison spécifique, sa préparation, sa purification et méthode de détection l'utilisant
EP0372352A3 (en) * 1988-12-06 1990-09-26 Chisso Corporation Aequorin fused with a protein having a specific-binding activity, its preparation, its purification and detection method by its use
WO1991009125A1 (fr) * 1989-12-07 1991-06-27 British Bio-Technology Limited Proteines et acides nucleiques
WO1991011454A1 (fr) * 1990-01-24 1991-08-08 The Upjohn Company Procede de purification de polypeptides recombines

Also Published As

Publication number Publication date
DK129085A (da) 1985-09-23
KR850006550A (ko) 1985-10-14
JPS60214897A (ja) 1985-10-28
DE3410437A1 (de) 1985-09-26
CA1230840A (fr) 1987-12-29
DK129085D0 (da) 1985-03-21
IL74661A0 (en) 1985-06-30

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Inventor name: KUTZBACH, CARL, DR.